Fragment screening for a new cavity

After about six months or so of having given up on automated docking I have returned with a new biological problem to explore.

I have recently solved the structure of a protein "that shall remain nameless" because I think I have identified a new pocket that no one has targeted before. After asking advice from the ccp4 bulletin board someone suggested using the Uppsalla Software Factories program "Voidoo" for better defining my cavity (http://xray.bmc.uu.se/usf/). As I am quite familiar with USF programs (although have never used Voidoo before) I was quickly able to make a map of all the cavities in my protein using a 1A probe, that I was then able to view in Coot. This gave me an excellent idea of the extent of the pocket along with some ideas of molecules that might fit it.

Before getting out all my Autodock and FlexX scripts again for compound screening I thought I would try out a webservice called "DOCK blaster" based on the docking program DOCK and the ZINC database. It was ridicuously simple to read in my pdb file (with waters and other ligands removed) and equally simple to define the protein site to be docked by simply placing a "fake" phosphate residue into my newly identified cavity and then giving DOCK blaster these coordinates. In a couple of hours I was able to screen three or four sub-sections of the ZINC database and get back fifty or so potential small molecules which, on inspection, seem to fit the site quite well.

I am really impressed with DOCK blaster as it managed to achieve in ten minutes something that took me hours to do last year. Although I have yet to validate the results, it has given me a start. I think the next thing will be to take these fragments and see what Autodock, FlexX and Gold make of them.